1-substituted-4-aminopiperazines and method of preparing the same



. .Patented Dec. 22,1953

1fsUBsTI'rUTED-4-AMiNoPiPEitAzNEs-ND v-ME'-rnon oF PREPARINGr THEEdwardA `A. iConr'oy, Plainfield, Nr-J., iassigno'r;4 to `-AmericanCyanamid Company, V.New rYork,

'y N'. Y., alcorporation of HMaine ...No-Drawing.. Application June 22,1951,

Serial-No. 2335124 'This invention relates ,toV new organic compounds.Morefjparti'culazlyjit `relatesto l-,substituted-@aminopiperazines andmethods of .preparing the fsame. v

The compounds `of then present invention 'may be illustrated by' thefollowing Ageneral'formula:

in which R is an alkyl, aryl, aralkyl, dialkylcarbamyl 'or nitrogencontaining *Y heterocyclic radical and Rand .R arehydrogen Aor a loweralkyl radical. Y

In general the. lfr eei amino compounds `of .the present inventiona'relow meltingsolids, many of which are actually liquid. atroomfte'mperature. They are, in general, slightly soluble. in petroleumether or petroleum benzene but readily soluble in Water, lower aliphaticalcohols, chloroform and the like. y

The new compounds of the 'present invention are preferably .preparedby51'eacting .a 1 substi tuted piperazine'with nitrous `acid'toflproclucethe 1-substitutedei-nitrosopiperazinefwhichv is subsequentlyreducedftogive thefdesired lsubstituted-v 4aminopiperazines.

As indicated above,. :the V,intermediates iny the present invention,.namely the .1l-substituted piperazines, may :bethQsezin-'vvhich thelsubstitu ent .is an alkyhgroupfsuch vasv methyl, ethyl, propyl, butyl,.and the like, ior `an .aryl'radicalsuch as,v phenyl,chlorophenyl-,-fnitrophenyl,.and the like, -nr an aralkyl radicalAsuch-,-as.;.tl1e .benz-yl, phenethyl and benzhydryl radicals on anitrogen containing` heterocyclic .radical suchias. pyrjdyl,pyrimidylgpyrazinyl;fthiazolylfet The ,piperv azine 'ring-may alsocontain one4 ormureflower;

alkyl substituents on the 2- and 5,- ca1tbon` atoms thereof, such asmethyl, ethyl, propyl, and the like.

Although the reductionY ofi the.l,.substituted 4-nitrosopiperazinespifjepared inthe process of the present invention 'may be accomplishedby catalytic means, Iv prefer nto use va .chemical method. Thepreferredfmethodis reductionfwith an acidrand a; metal, for; example,:zinci dust :and

acetic acid, tin and hydrochloric.acid-etc. The

reduction .is preferably-carried.- 'out in;l Water or lower aliphaticalcohols vlorzmixturesfiof y Waterand such alcohols) at Va temperaturevof vfrom e109. v to 30 C. Other chemical methods may be usedpin thereduction of the 1,-substituted-t-nitroso temperature.' Thefcoinhydroxideiis redissolv viv.,

215 claims. (c1. 26o-256.4)

tion or, 6 infsome-:nasesg'iby recrystalliZtion-'f y solvents such .aspetroleum `ether Ior" naphtha;

As the 1-substitutedmlearninopiperazinesHof the present invention arebasic in character, due

., to the presence of an ax'ii-inoigroup, they will form stable addition.salts.Withacidsl .To-form-asalt of the ffree base. iti s.pre:f.e rableto treat a solution of the bas'in a lowerwaliphatic alcoholwithasolution of the acid inlwater er 'Itter aliphatic alcohol. If theacid isaj gas, it may simply be bubbled through the :solutionoofrthe' base Inlih" the l-substitutedl-aminopiperazines"to i'i'm 1 Lammel-)inerenteffii afnemende, :are :aigre scopic.

The '1-substitutcd-4-aminopperazines of the compounds of Athe presentinvention are useful as intermediates in the preparation of thecompounds of my copending application, Serial Number 233,125, filed June22, 1951 and also of a copending application of which I am coinventorwith R. P. Parker, Serial Number 233,126, led June 22, 1951. t

The examples which follow illustrate the general process of the presentinvention for Y the preparation of 1substituted-4-aminopiperazines andsalts of such compounds.

EXAMPLE 1 To a solution of 100 parts of 1-(4-chlorophenyl) -piperazinein 400 parts of water is added 36% aqueous hydrochloric acid until thesolution is acidic to Congo Red paper. The temperature of this solutionis maintained at 'ZW-75 C., with stirring, while a solution of 35 partsof sodium nitrite in 50 parts of water is added dropwise over a periodof one hour. The material which separates during the course of theaddition is isolated. This material, 1-(4-chlorophenyl) -4-nitrosopiperazine, when crystallized from absolute ethanol, melts at9495 C.

By following the above procedure and substituting for the1-(4-chloropheny1) piperazine an equivalent amount of the compoundlisted in column 1 of the table below, the corresponding 4-nitrosocompound, whose properties are listed in columns 2 and 3 of the table,is obtained.

In a solution of 750 parts of glacial acetic acid and '750 parts ofwater is suspended 225 parts of 1-(4-chlorophenyl) -4-nitrosopiperazine.The temperature of the slurry is maintained at 25.",-30D C., withstirring, while 200 parts of zinc dust is added portionwise over aperiod of onehalf hour. Then the temperature of the reaction mixture ismaintained at 50 C. for one hour. The reaction mixture is filtered andto the filtrate is added 2,300 parts of 50% aqueous sodium hydroxidesolution. The product is extracted with chloroform and the solvent isremoved from the extract by distillation. The residue is crystallizedfrom petroleum benzene. The product, 1-(4-chlorophenyl)-4-aminopiperazine, melts at 87.5-89.0 C.

1 The temperature of the solution is maintained at 15 C. instead of 70-75 C. for the nitrosation of this compound.

2'Ihis product does not separate from the solution but may be extractedwith a `solvent such as chloroform.

4 EXAMPLE 2 1-(4-chlorophenyl) -4-aminopiperazine benacate In 160 partsof absolute ethanol is dissolved 10.6 parts of1-(4-chlorophenyl)4-aminopiper azine and 6.1 parts of benzoic acid.rlFhe solution, on cooling, deposits white crystals of l-(4-chlorophenyl) 4 aminopiperazine benzoate which melts at 130.5-131.5 C.

EXAMPLE 3 1 (Z-pyridyl) -4-aminopiperaaz'ne In a solution of 400 partsof glacial acetic acid and 600 parts of water is dissolved 192 parts of1 (Z-pyridyl) 4 nitrosopiperazine (see the table, Example 1 above). thesolution is maintained at 25-30 C., with stirring, while 200 parts ofzinc dust is added portionwise over a period of one hour. Then thetemperature of the reaction mixture is maintained at 60 C. for one-halfhour. The reaction mixture is ltered and to the iilterate'is added 1,500parts of 50% aqueous sodium hydroxide solution. The product is extractedwith chloroform and the solvent is removed from the extract bydistillation. The residue is distilled at 15.0 mm. andthe fractionboiling at 175-180 C. is collected as product. The product,1-(2-pyridyl) 4-aminopiperazine, when crystallized from a mixture ofabsolute ethanol and petroleum benzene, melts at '76-78 C.

EXAMPLE 4 1-(2-pyrdyl)-4-aminopiperazine benzoate EXAMPLE 5 1(2pyrimz'dyl) -4-aminopiperazine In a solution of 385 parts of glacialacetic acid and 490 parts of water is dissolved-167 parts of 1-(2pyrimidyl) 4 nitrosopiperazine (see the table, Example 1 above). Thetemperature of the solution is maintained at 25-30'i C., with stirring,while 172 parts of zinc dust is added portionwise over a period of onehour. Then the temperature of the reaction mixture is maintained at 40C. for one-half hour. The reaction mixture is filtered and to thefiltrate is added 1,500 parts of 50% aqueous sodium hydroxide solution.The product is extracted with chloroform and the solvent is removed fromthe extract by distillation. The residue is distilled at 1.0 mm. and thefraction boiling at 130 C. is collected as the product,1-(2-pyrlmidyD-4- aminopiperazine.

EXAMPLE 6 1 (Z-pyrimidyl) -4-am1iopiperazinc hydrochloride In parts ofabsolute ethanol is dissolved 30 partsV ofI-(Z-pyrimidyl)-4-aminopiperazine and 16.5 parts of 36% aqueoushydrochloric acid. The product separates as white crystals from thesolution. The product, 1-(2-pyrimidyD-4-- The temperature of droxidesolution. The product is extracted With Al chloroform and the solvent isremoved from the extraetfby., distillation.; Thearesidueiisr'disnlled.;at, atmospheric -`pressure Vandthe fraction-,boiling.. at 1'7.2l575?. C.is... collected .v as...- tha` product, 1methyl-4-aminopiperazine..

EXAMPLE'JSL 1-methyZ-4-aminopiperazine dziyclfochloride In 360 parts ofabsolute ethanol is dissolved partsofA 36% aqueuushydrochloric. acid..The,v product 'separates j as ,White crystals. from the solution... Theproduct, L 1,-'methylj-4 laminonipel azine dihydrochloride; whenrecrystallized "from absolute ethanol, melts at..223.0225.0 C.

1 -dz'ethylcarb amyl-i4-amnopiperazine In a solution of 300parts ofglacial acetic acid anarco.partsoewaterisdissolved.itamaristfl-diethylcarbamylfinitrosopiperazine... (seeetha. table, Example. `.1above) Tlietemperature..of .i the solution .is maintainedrat y,25E-C,... ,with stirring... while 200-.parta `of.zinlc.,dust.`is.sar;ded.l,portionwise over a period of one hour. Thenthef-etemperaturefofathefreaction mixture is maintained at 60 C.` for one-halfhour. The reaction mixture is Iilteredfand-to.\thefiltrate is added1,140 parts of 50% aqueous sodium hydroxide solution. The product isextracted with chloroform and the solvent is removed from the extract bydistillation. The residue is distilled at 6.0 mm. and the fractionboiling at 148150 C. is collected as the product,l-diethylcarbamyl-l-aminopiperazine.

EXAMPLE 10 1-diethylcarbamyl-4-aminopiperazine pzcrate In 370 parts ofabsolute ethanol is dissolved 20zu.;1a(Bathiazolyl1-4enitrosopiperazin'Mseedzhetable.

issextmcteddwithlzehtnrodnnuadthesolventtis removed from the extract bydislfllltori;- 'If-fiez` residue is distilled at 4.0mm. and the fractionboiling at 135-1385Ci's collectedias the product,1benzyl-4-aminopiperazinef Y Em f "121. 1.abenaglanminnpiperaemeebenoateiesepartsofabsolte ethanol' is vdirsonedfz' 10?parts'crianzynifammcpiperazine and rslpart's solyentaisremovedfromz'thefextaactby l'distlllav f tionm.Thearesiduecisidistilled:atulumnmsandithe fraction boiling at 125-1 30C. is cullefeted'iasithef product;1=atlliazolyleinaminolzlip'erazirieg;y

EXAlV/IPISIET.'14

1-(2-th11aeolyl) -4-aminopipera'zine dihydrochloride In 120 parts ofabsolute ethanol is dissolved 2'7 @parts of .1-(2-thiazoly1').-:4-aminopiperazinerand-;

14fpartsofi'369i`aqueous hydrochloric acicLl The.v l product'separates'aswlit' crystals'trm .the.solu. tiont vTheun productif,1J(thiazolyllAamincipiperazine**diiiydiochldride' when recrystalli'zedfrom 95% aqueous ethanol, melts at 229-231 C With decomposition.

I claim:

1. Compounds of the group having the formula:

2. Compounds of the group having the formula:

parts of 1-diethylearbamyl-4-aminopiperazine 55 l and 23 parts of picricacid. The product separates as yellow crystals from the solution. Theproduct, l-diethylcarbamyl -4- aminopiperazine picrate, whenrecrystallized from absolute ethanol, melts at 134.0135.0 C.

EXAMPLE 11 1-benzyl-4-aminopperazine in which R is a. monocyclic arylradical.

3. 1-benzyl-4-aminopiperazine.

4. 1- (4-chlorophenyl) -4-aminopiperazine.

5. l-(z-pyrimidyl) -4-aminopiperazine.

6. 1-methyl-4-aminopiperazine. Y

7. 1fdiethylcarbamyl-l-aminopiperazine.

8. A method of preparing compounds having the general formula:

in which R is a monocyclic aralkyl radical which comprises reacting a1-monocyclic-aralkyl-piperazine With an alkali 'metal nitrite andamineral acid to produce a 1-monocyclic-aralkyl- 4-nitrosopiperazine,subsequently reducing said nitrosopiperazine with a metal and an acidand recovering sai-d 4-aminopiperazine therefrom.

:general formula:

:in which R is a monocyclic .aryl radical which comprises reacting a1-monocyclic arylpiperazine with an alkali metal nitrite and a mineralacid to produce a 1-monocyclic aryl--nitrosopiperazine, subsequentlyreducing said nitrosopiperazine with a metal and an acid and recoveringsaid 4-aminopiperazine therefrom. Y

10. A method of preparing 1-benzyl-4-aminopiperazine which comprises thestep of reducing 1benzyl4-nitrosopiperazine with zinc dust and aceticacid and recovering, said 1-benzyl4-aminopiperazine therefrom. v

11. A method of preparing 1-(4-chlorophenyl) 4-aminopiperazine whichcomprises the step of reducing 1- (4-chlorophenyl) -4-nitrosopiperazinewith acetic acid and zinc and recovering said 1- (4-chlorophenyl)-4-aminopiperazine therefrom.

12. A method of :preparing l(2-pyrimidyl) 4-aminopiperazine whichcomprises the step of reducing 1 (2 pyrimidyl) 4nitrosopiperazine withacetic acid andzinc and recovering said 1- (Z-pyrimidyl)-4-aminopiperazine therefrom.

13. A method of preparing 1-methyl-4-aminopiperazine which comprises thestep of reducing 1-methyl-4-nitrosopiperazine with acetic acid and zincand recovering said 1methy14aminopiper azine therefrom.

14. Compounds of the group consisting of those having the generalformula:

in which R is a member of the group consisting of lower alkyl,monocyclic aralkyl, dicyclic aralkyl, monocyclic aryl, di-loweralkylcarbamyl, pyridyl, pyrimidyl and thiazolyl radicals in which thebond from the nitrogen inthe piperazine ring to the heterocyclic ring isto a group and R' and R" are members of the group consisting of hydrogenand methyl radicals and acid addition salts thereof.

15. A method of preparing compounds having the general formula:

in which R is a member of the group consisting of lower alkyl,monocyclic aralkyl, dicyclic aralkyl, monocyclic aryl, di-loweralkylcarbamyl, pyridyl, pyrimidyl and thiazolyl radicals in which thebond from the nitrogen in the piperazine ring to the heterocyclic ringis to a group and R' and R" are members of the group consisting ofhydrogen and methyl radicals which comprises reacting a compound havingthe formula in which R, R' and R" are as defined above with an alkalimetal nitrite in a mineral acid to produce the correspondingl-substtuted-li-nitrosopiperazine, subsequently reducing saidnitrosopiperazine and recovering said ll-aminopiperazine therefrom.

' EDWARD A. CONROY.

No references cited.

8. A METHOD OF PREPARING COMPOUNDS HAVING THE GENERAL FORMULA: 14.COMPOUNDS OF THE GROUPS CONSISTING OF THOSE HAVING THE GENERAL FORMULA: